Ellis-Van Creveld Syndrome and Dandy-Walker Malformation: An Uncommon Association.

Ellis-Van Creveld (EvC) syndrome is a rare autosomal recessive chondroectodermal dysplasia including chondrodysplasia, postaxial polydactyly, ectodermal dysplasia, and congenital heart disease in 60% of patients. Additional findings may be observed affecting the pulmonary, renal, gastrointestinal, hematologic, and central nervous systems. We report a case of an 11-year-old Moroccan boy with EVC syndrome and Dandy-Walker malformation. To our knowledge, this association has been previously reported in 3 patients in the literature.

[Williams-Beuren syndrome: a retrospective study of a series of 11 cases at the Mohammed VI University Hospital in Marrakech]. / Syndrome de Williams-Beuren: étude rétrospective d'une série de 11 cas du Centre Hospitalier Universitaire Mohammed VI de Marrakech.

Williams-Beuren syndrome is a rare genetic disease (1/20 000) characterized by a microdeletion at 7q11.23 encompassing about 28 genes, including the elastin gene, ELN. It is a sporadic disease in the majority of cases. Easily identifiable in childhood, this developmental disorder associates suggestive face dysmorphism, cardiac defect, psychomotor retardation and specific behavioural and cognitive profile. We conducted a retrospective study of 11 patients with Williams-Beuren syndrome whose data were collected in the Genetics Department of the Mohammed VI University Hospital of Marrakech. The average age of patients was 6.05 years (SD=6.56; interquartile range=5), with a female predominance (64%; 7/11 patients). Almost all patients were mentally retarded and the diagnosis was confirmed in 100% (11) of patients using fluorescence in situ hybridisation (FISH).

[Contribution of cytogenetic in the diagnosis of Edwards's syndrome: about 9 cases]. / Apport de la cytogénétique dans le diagnostic du syndrome d'Edwards : à propos de 9 cas.

INTRODUCTION: Trisomy 18 is a constitutional chromosomal disorder defined by the presence of a supernumerary chromosome 18. The diagnosis is suspected clinically and confirmed by cytogenetic analysis. Genetic counseling for patients' families is important. The objective of this study is to report our experience in Medical Genetics Department at the Mohammed VI University Hospital of Oujda in the diagnosis and genetic counseling of trisomy 18 through dysmorphological expertise and cytogenetic analysis. MATERIAL AND METHODS: We report a retrospective descriptive study over a period of four years (2018-2022) of nine patients with polymalformative syndrome suggestive of trisomy 18 who underwent cytogenetic analysis. RESULTS: The median age of patients at diagnosis was 2 days with a male predominance. The mean maternal age at birth of the patients in our series was 40 years. Consanguinity was found in only one patient. All patients had a typical phenotype of trisomy 18. The postnatal constitutional karyotype showed a homogeneous trisomy 18 in all patients. In our series, only one patient is still alive at the age of 7 months, the other 8 patients died with a median postnatal survival of 5 days. CONCLUSION: We underline through this study, the contribution of the medical geneticist in the clinic and cytogenetic diagnostic approach of rare chromosomal affections, in order to provide an adequate genetic counseling to the families.

An inherited LMNA gene mutation in atypical Progeria syndrome.

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis of HGPS is based on the recognition of common clinical features and detection of the recurrent heterozygous c.1824C>T (p.Gly608Gly) mutation within exon 11 in the Lamin A/C encoding gene (LMNA). Besides "typical HGPS," several "atypical progeria" syndromes (APS) have been described, in a clinical spectrum ranging from mandibuloacral dysplasia to atypical Werner syndrome. These patients's clinical features include progeroid manifestations, such as short stature, prominent nose, premature graying of hair, partial alopecia, skin atrophy, lipodystrophy, skeletal anomalies, such as mandibular hypoplasia and acroosteolyses, and in some cases severe atherosclerosis with metabolic complications. APS are due in several cases to de novo heterozygous LMNA mutations other than the p.Gly608Gly, or due to homozygous BAFN1 mutations in Nestor-Guillermo Progeria syndrome (NGPS). We report here and discuss the observation of a non-consanguineous Moroccan patient presenting with atypical progeria. The molecular studies showed the heterozygous mutation c.412G>A (p.Glu138Lys) of the LMNA gene. This mutation, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.

Clinical description and mutational profile of a Moroccan series of patients with Rubinstein Taybi syndrome.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is a rare autosomal dominant developmental disorder with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical face, broad thumbs and halluces, short stature, and intellectual disability. Facial dysmorphy is characteristic with microcephaly, low frontal hairline, arched eyebrows, long eyelashes, convex profile of nose, narrow palate, and micrognathia. RSTS is mainly due to mutations or microdeletions of the CREBBP gene (about 60%) and more rarely of the EP300 gene (8%). OBJECTIVE: Clinical description and identification of mutations of patients with Rubinstein Taybi syndrome. METHODS: PCR and direct sequencing of CREBBP gene. RESULTS: We report here, the clinical and molecular data of a series of six Moroccan patients with a phenotype of RSTS. The molecular study of the major gene CREBBP (by Sanger Sequencing followed by CGH array, if sequence normal) revealed point mutations in five patients. For the sixth patient, CGH array revealed a microdeletion carrying the CREBBP gene. Through this work, we emphasize the importance of clinical expertise in the diagnosis, management and genetic counseling in Rubinstein Taybi syndrome.

Patients' Knowledge and Attitude Toward Biobanks in Eastern Morocco.

Background: To integrate biobanks into the Moroccan health system and to promote biobanks-based research projects, it is necessary to explore the knowledge of patients, their attitudes toward biobanks, and the reasons that motivate them to participate in biobanks. Methods: Face-to-face interviews were conducted with patients, and data were analyzed using SPSS. Results: One thousand one hundred thirty-three questionnaires were completed. The mean age of patients was 47.74 years (SD 15.26 years). More women (69%) were involved in this survey. Of the respondents, 97% had never heard of the term "biobanks." Knowledge of biobanks varied significantly with respondents' education level. Overall, 80.7% of the participants (n = 914) expressed their willingness to participate in biobanking through donation of biospecimens associated with personnel and health data. Willingness to participate in biobanks was significantly associated with gender and age. We found that the main barriers to participation in biobanks were the lack of trust in biomedical research and concerns about privacy. When asked about the preferred type of consent, the majority of patients (75%) opted for a one-time consent. Conclusion: Despite the lack of knowledge of biobanks among patients in Eastern Morocco, the majority of them expressed willingness to participate in biobanking through donation of biospecimens. However, active participation depended upon a number of factors, notably, the trust in biomedical research and privacy. Therefore, more efforts are needed to increase awareness and promote wider participation in biobanking.

Morocco's First Biobank: Establishment, Ethical Issues, Biomedical Research Opportunities, and Challenges.

BACKGROUND: Biobanks are highly organized infrastructures that allow the storage of human biological specimens associated with donors' personal and clinical data. These infrastructures play a key role in the development of translational medical research. In this context, we launched, in November 2015, the first biobank in Morocco (BRO Biobank) in order to promote biomedical research and provide opportunities to include Moroccan and North African ethnic groups in international biomedical studies. Here, we present the setup and the sample characteristics of BRO Biobank. METHODS: Patients were recruited at several departments of two major health-care centers in the city of Oujda. Healthy donors were enrolled during blood donation campaigns all over Eastern Morocco. From each participant, personal, clinical, and biomedical data were collected, and several biospecimens were stored. Standard operating procedures have been established in accordance with international guidelines on human biobanks. RESULTS: Between November 2015 and July 2020, 2446 participants were recruited into the BRO Biobank, of whom 2013 were healthy donors, and 433 were patients. For healthy donors, the median age was 35 years with a range between 18 and 65 years and the consanguinity rate was 28.96%. For patients, the median age was 11 years with a range between 1 day and 83 years. Among these patients, 55% had rare diseases (hemoglobinopathies, intellectual disabilities, disorders of sex differentiation, myopathies, etc.), 13% had lung cancer, 4% suffered from hematological neoplasms, 3% were from the kidney transplantation project, and 25% had unknown diagnoses. The BRO Biobank has collected 5092 biospecimens, including blood, white blood cells, plasma, serum, urine, frozen tissue, FFPE tissue, and nucleic acids. A sample quality control has been implemented and suggested that samples of the BRO Biobank are of high quality and therefore suitable for high-throughput nucleic acid analysis. CONCLUSIONS: The BRO Biobank is the largest sample collection in Morocco, and it is ready to provide samples to national and international research projects. Therefore, the BRO Biobank is a valuable resource for advancing translational medical research.

[Lung cancer in Eastern Morocco: where do we stand?] / Cancer du poumon au Maroc Oriental: où en sommes-nous?

INTRODUCTION: Lung cancer is the most common cancer in men living Eastern Morocco. We here present the first report on the clinical, pathological and therapeutic features of lung cancer in Eastern Morocco. METHODS: We conducted a retrospective study of 738 patients diagnosed with lung cancer at the Hassan II, Oncology Center between October 2005 and December 2014. RESULTS: Among the cases studied, 671 patients were men and 67 women; 95.01% of men and 1.54% of women were smokers. The average age of patients was 59.1 ± 11.9 years. Most patients (97%) were diagnosed at advanced stage disease. Only 4 out of 227 patients with advanced adenocarcinoma underwent molecular test. In addition, no patient in our series received targeted therapy. In this series, 20.46% of patients had less than 50 years. Compared to patients aged 50 years and older, cannabis consumption was higher (p<0.001) in patients less than 50 years and as well as a higher rate of adenocarcinoma (p<0.01). By contrast, in these patients, tobacco consumption was lower (p<0.001) as well as the rate of squamous cell carcinoma (p<0.01) and small cell cancer (p<0.05). CONCLUSION: Unlike Western countries, in Eastern Morocco lung cancer is diagnosed late, affects younger people and access to molecular tests is still very limited. These results justify the need to implement effective programs against lung cancer as well as to facilitate access to molecular tests and new therapeutic tools in Eastern Morocco.

AGXT Gene Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population.

INTRODUCTION: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by deficiency of alanine glyoxylate aminotransferase, due to a defect in the AGXT gene. Several mutations in this gene have been reported and some of them have been observed in multiple populations. The aim of our study was to analyze the mutations causing PH1 in the Moroccan population and to estimate its prevalence in Morocco. METHODS: Molecular studies of 29 unrelated Moroccan patients with PH were performed by direct sequencing of all exons of the AGXT gene. In addition, to estimate the prevalence of PH1, we screened for the recurrent p.Ile244Thr mutation in 250 unrelated Moroccan newborns using real-time polymerase chain reaction. RESULTS: Four pathogenic mutations were detected in 25 unrelated patients. The c.731T>C (p.Ile244Thr) was the most frequent mutation with a frequency of 84%. The other three mutations were c.33delC, c.976delG, and c.331C>T. The prevalence of the PH1 mutation among Moroccans was then estimated to range from 1/7267 to 1/6264. CONCLUSION: PH1 is one of the most prevalent genetic diseases in the Moroccan population and is probably underdiagnosed. Front line genetic testing for PH1 in Morocco should be initiated using an assay for the recurrent p.Ile244Thr mutation. This strategy would provide a useful tool for precocious diagnosis of presymptomatic individuals and to prevent their rapid progression to renal failure.

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.

Germline mosaicism in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome is an autosomal dominant disorder with multiple congenital anomalies and genetic heterogeneity. Clinical manifestations include mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and characteristic facial features. Mutations in the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP; OMIM 600140) on chromosome 16p13, account for about 50% to 70% of patients. Most of CREBBP mutations are de novo and the rate of recurrence in a family is low. Families with several affected children are extremely rare. We report here a Moroccan family with two children with RSTS and apparently unaffected parents. The molecular studies showed a heterozygous mutation c.4361T>A (p.Leu1454His) in exon 26 of the CREBBP gene in the two affected siblings. Neither the parents, nor the healthy brother, carry this mutation in hematologic cells. The mutation was also absent in buccal epithelial cells of both parents. We discuss the hypothesis of germinal mosaicism. This concept is very important because it complicates genetic counseling of this family who has a risk of recurrence of the mutation in subsequent pregnancies.

Frequency of IL28B rs12979860 single-nucleotide polymorphism alleles in newborn infants and in patients with chronic hepatitis C in Morocco.

BACKGROUND: Epidemiological and experimental evidence support the role of host genetics in treatment response and viral clearance in chronic hepatitis C (CHC). Recently, the CC genotype of IL28B single-nucleotide polymorphism (SNP) rs12979860 has been associated with spontaneous viral clearance and a better treatment response. The distribution of this polymorphism varies according to populations. Frequency of rs12979860 SNP alleles in the Moroccan population is unknown. The aim of our study was to estimate the frequency of the C allele of this SNP in the Moroccan population and, in parallel, in a cohort of Moroccan patients with CHC treated with pegylated interferon-alpha and ribavirin. METHODS: We used real-time polymerase chain reaction assay based on TaqMan technology to determine the allele frequency of the rs12979860 SNP in 100 Moroccan newborn infants. We also compared the frequency of the CC genotype between two groups of patients with genotype 1-CHC treated by combination therapy: group1, n=30 patients, responders who achieved sustained viral response (SVR) and group2, n=30 patients, nonresponders. RESULTS: The rs12979860 C allele frequency was estimated to be 73% in the Moroccan population. The frequency of this allele in the group of patients with CHC was only 58.3%, and the CC genotype is more prevalent in group1 (62.5%) than in group 2. CONCLUSIONS: This is the first report providing genetic data related to the frequency of genetic polymorphisms of IL28B in Morocco. The C-allele frequency of the IL28B gene SNP rs12979860 in Morocco is higher than in the African populations. Distribution of this SNP distinguishes in a population of CHC between SVR and nonresponders. This result merits consideration and should be studied by analyzing a larger sample size of patients.

Pyruvate dehydrogenase deficiency caused by a new mutation of PDHX gene in two Moroccan patients.

Pyruvate dehydrogenase deficiency is one of the genetic defects of mitochondrial energy metabolism. Clinical features are heterogeneous, ranging from fatal lactic acidosis in the newborn period to chronic neurodegenerative abnormalities. Most cases have mutations in the gene for the E1alpha subunit of the pyruvate dehydrogenase complex. Primary defects of the E3 binding protein component of the pyruvate dehydrogenase complex are rarier. We describe two unrelated Moroccan patients with the same new mutation c.1182 + 2T > C in the E3 binding protein gene PDHX and different clinical forms.